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1α,25‐dihydroxyvitamin D 3 ‐mediated stimulation of steroid sulphatase activity in myeloid leukaemic cell lines requires VDR nuc ‐mediated activation of the RAS/RAF/ERK‐MAP kinase signalling pathway
Author(s) -
Hughes Philip J.,
Brown Geoffrey
Publication year - 2006
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.20787
Subject(s) - kinase , mapk/erk pathway , map kinase kinase kinase , chemistry , protein kinase a , mitogen activated protein kinase kinase , biology , microbiology and biotechnology , biochemistry
1α,25‐dihydroxyvitamin D 3 (1α,25(OH) 2 D 3 ) stimulates the activity of steroid sulphatase (STS) in myeloid cells [Hughes et al., 2001, 2005]. This was attenuated by inhibitors of phospholipase D (PLD) ( n ‐butanol, 2,3‐diphosphoglyceric acid, C 2 ‐ceramide) and phosphatidate phosphohydrolase (PAP) (propranolol and chlorpromazine), but was unaffected by inhibitors of phospholipase C. The 1α,25(OH) 2 D 3 ‐induced STS activity was also attenuated by inhibitors of protein kinase Cα and protein kinase Cδ (Go 6976, HBDDE and rottlerin), but not by an inhibitor of protein kinase Cβ (LY379196). Additionally, 1α,25(OH) 2 D 3 ‐induced STS activity was attenuated by inhibitors of RAS (manumycin A), RAF (GW5074), MEK (PD098059 and U1026) and JNK (SP600125), but not p38 (PD169316). 1α,25(OH) 2 D 3 produced a rapid and long lasting stimulation of the ERK‐MAP kinase signalling cascade in HL60 myeloid leukaemic cells. This ‘non‐genomic’ effect of 1α,25(OH) 2 D 3 blocked by pharmacological antagonists of nuclear vitamin D receptors (VDR nuc ) and does not appear to require hetero‐dimerisation with the retinoid‐X receptor (RXR). Inhibitors of the Src tyrosine kinase (PP1), RAS (manumycin A), RAS–RAF interactions (sulindac sulphide and RAS inhibitory peptide), RAF (GW5074 or chloroquine), and protein kinase Cα (HBDDE) abrogated the 1α,25(OH) 2 D 3 ‐stimulated increase in ERK‐MAP kinase activity. Taken together, these results show that 1α,25(OH) 2 D 3 /VDR nuc activation of the RAS/RAF/ERK‐MAP kinase signalling pathway plays an important role in augmenting STS activity in human myeloid leukaemic cell lines. J. Cell. Biochem. 98: 590–617, 2006. 2006 Wiley‐Liss, Inc.